Competitive intramolecular C-C vs. C-O bond coupling reactions toward C6 ring-fused 2-pyridone synthesis.

An interesting competitive C-C vs. C-O bond coupling reaction on N,3,5-trisubstituted pyridones is reported. These coupling reactions provided selective access to C- or O-ring-fused pyridones, both at the challenging C6-pyridone position. 1,6-C-Annulated pyridones were generally achieved in good yields with excellent chemoselectivity under Pd(0) conditions. On the other hand, full C6-regioselective Csp(2) aryloxylation was achieved under oxidative coupling promoted by silver salts to access 5,6-O-annulated pyridones. Based on various experiments and observations, mechanistic evidence of these competitive reactions was provided and it was proposed that C-O bond formation proceeded through radical cyclization. These processes were performed under mild reaction conditions and offer an efficient and attractive methodology to selectively access a large scope of C-arylated and O-arylated pyridones of biological interest.

A Boy with Holt-Oram Syndrome Caused by Novel Mutation c.1304delT in the TBX5 Gene.

Holt-Oram syndrome (HOS) is an autosomal dominant developmental defect involving preaxial radial ray upper limb deformity and variable cardiac defects. It has been demonstrated that HOS is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 60) of this gene produce preterminal stop codons, which lead to synthesis of a truncated nonfunctional TBX5 protein. The haplo-insufficiency of the TBX5 gene is the most significant cause of HOS. We report on a sporadic patient with clinical features of HOS. Our patient had a cardiac anomaly - a muscular ventricular and atrial septal defect, patent ductus arteriosus and a conduction defect (a first-step atrioventricular block). Upper limb anomalies in our patient were relatively mild and unusual to HOS - distally displaced thumbs, narrow shoulders and hypotrophy of the muscles in the shoulder region. Molecular analysis identified a novel and unusual heterozygous frameshift mutation - c.1304delT (p.Leu435fsX146) - in exon 9 of the TBX5 gene, which is predicted to cause an elongated TBX5 protein with 84 miscoding amino acids and 62 supernumerary C-terminal amino acids. To the best of our knowledge, only one such type of elongation mutation has thus far been reported in the TBX5 gene.

A novel mutation in the M1S1 gene responsible for gelatinous droplike corneal dystrophy.

PURPOSE: To identify the genetic defect in the M1S1 gene causing gelatinous droplike corneal dystrophy (GDLD) in an Estonian family. METHODS: DNA was extracted from members of a GDLD-affected family and control persons. Polymerase chain reaction followed by direct sequencing was used to detect mutations in the M1S1 gene. Sequencing results were confirmed with restriction analysis. RESULTS: Sequencing of the M1S1 gene revealed a novel mutation and a common polymorphism. All patients with GDLD were found to be homozygous for the insertion of nucleotide C in position 520 in M1S1. The mutation leads to formation of truncated protein. The mutation was excluded in 103 normal, unaffected individuals. Very close to the location where the mutation was identified in the M1S1 gene, a single-nucleotide polymorphism (518A/C) was found, changing aspartic acid to alanine at codon 173. CONCLUSIONS: The data indicate that mutation ins520C in the M1S1 gene is the primary cause of GDLD in the family studied.